Background The ongoing COVID-19 pandemic warrants accelerated efforts to test vaccine candidates. We aimed to assess the safety and immunogenicity of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate, BBIBP-CorV, in humans.Methods We did a randomised, double-blind, placebo-controlled, phase 1/2 trial at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan Province, China. In phase 1, healthy people aged 18-80 years, who were negative for serum-specific IgM/IgG antibodies against SARS-CoV-2 at the time of screening, were separated into two age groups (18-59 years and ≥60 years) and randomly assigned to receive vaccine or placebo in a two-dose schedule of 2 μg, 4 μg, or 8 μg on days 0 and 28. In phase 2, healthy adults (aged 18-59 years) were randomly assigned (1:1:1:1) to receive vaccine or placebo on a single-dose schedule of 8 μg on day 0 or on a two-dose schedule of 4 μg on days 0 and 14, 0 and 21, or 0 and 28. Participants within each cohort were randomly assigned by stratified block randomisation (block size eight) and allocated (3:1) to receive vaccine or placebo. Group allocation was concealed from participants, investigators, and outcome assessors. The primary outcomes were safety and tolerability. The secondary outcome was immunogenicity, assessed as the neutralising antibody responses against infectious SARS-CoV-2. This study is registered with www.chictr.org.cn, ChiCTR2000032459. FindingsIn phase 1, 192 participants were enrolled (mean age 53•7 years [SD 15•6]) and were randomly assigned to receive vaccine (2 μg [n=24], 4 μg [n=24], or 8 μg [n=24] for both age groups [18-59 years and ≥60 years]) or placebo (n=24). At least one adverse reaction was reported within the first 7 days of inoculation in 42 (29%) of 144 vaccine recipients. The most common systematic adverse reaction was fever (18-59 years, one [4%] in the 2 μg group, one [4%] in the 4 μg group, and two [8%] in the 8 μg group; ≥60 years, one [4%] in the 8 μg group). All adverse reactions were mild or moderate in severity. No serious adverse event was reported within 28 days post vaccination. Neutralising antibody geometric mean titres were higher at day 42 in the group aged 18-59 years (87•7 [95% CI 64•9-118•6], 2 µg group; 211•2 [158•9-280•6], 4 µg group; and 228•7 [186•1-281•1], 8 µg group) and the group aged 60 years and older (80•7 [65•4-99•6], 2 μg group; 131•5 [108•2-159•7], 4 μg group; and 170•87 [133•0-219•5], 8 μg group) compared with the placebo group (2•0 [2•0-2•0]). In phase 2, 448 participants were enrolled (mean age 41•7 years [SD 9•9]) and were randomly assigned to receive the vaccine (8 μg on day 0 [n=84] or 4 μg on days 0 and 14 [n=84], days 0 and 21 [n=84], or days 0 and 28 [n=84]) or placebo on the same schedules (n=112). At least one adverse reaction within the first 7 days was reported in 76 (23%) of 336 vaccine recipients (33 [39%], 8 μg day 0; 18 [21%], 4 μg days 0 and 14; 15 [18%], 4 μg days 0 and 21; and ten [12%], 4 μg days 0 and 28). One placeb...
The pandemic of COVID-19 caused by SARS-CoV-2 has posed serious threats to global health and economy, thus calling for the development of safe and effective vaccines. The receptor-binding domain (RBD) in the spike protein of SARS-CoV-2 is responsible for its binding to ACE2 receptor. It contains multiple dominant neutralizing epitopes and serves as an important antigen for the development of COVID-19 vaccines. Here, we showed that immunization of mice with a candidate subunit vaccine consisting of SARS-CoV-2 RBD and Fc fragment of human IgG, as an immunopotentiator, elicited high titer of RBD-speci c antibodies with robust neutralizing activity against both pseudotyped and live SARS-CoV-2 infections. The mouse antisera could also effectively neutralize infection by pseudotyped SARS-CoV-2 with several natural mutations in RBD and the IgG extracted from the mouse antisera could also show neutralization against pseudotyped SARS-CoV and SARS-related coronavirus (SARSr-CoV). Vaccination of human ACE2 transgenic mice with RBD-Fc could effectively protect mice from the SARS-CoV-2 challenge. These results suggest that SARS-CoV-2 RBD-Fc has good potential to be further developed as an effective and broad-spectrum vaccine to prevent infection of the current SARS-CoV-2 and its mutants, as well as future emerging SARSr-CoVs and re-emerging SARS-CoV. Background The outbreaks of severe acute respiratory syndrome (SARS) caused by SARS coronavirus (SARS-CoV) in 2002/2003 and those of middle east respiratory syndrome (MERS) caused by MERS coronavirus (MERS-CoV) in 2012 have highlighted the high zoonotic potential of emerging coronaviruses 1, 2. The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel coronavirus 2019 (2019-nCoV) 3 , which was also denoted as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 4 , or human coronavirus 2019 (HCoV-19) 5 , has resulted in more than 17 million con rmed cases and 0.66 million deaths in 216 countries, areas or territories (https://www.who.int/), endangering the global public health and economy and thus calling for the development of effective vaccines to protect at-risk populations. Currently, more than 150 COVID-19 vaccines are under development at different stages 6-9. Especially, a number of COVID-19 vaccines' phase 1/2 clinical trials have been completed, including the adenovirusvectored vaccines (Ad5-nCoV and ChAdOx1 nCoV-19) from CanSino 10 and Oxford University/AstraZeneca 11 , respectively; the mRNA vaccines (mRNA-1273 and BNT162b1) from Moderna 12 and P zer/BioNTech 13 , respectively; and the inactivated vaccines (PiCoVacc and BBIBP-CorV) from Sinovac 14 and Beijing Institute of Biological Products 15 , respectively (https://biorender.com/covid-vaccine-tracker/). Generally speaking, all these vaccines could induce antibodies speci c for spike (S) protein and receptor-binding domain (RBD), which neutralized pseudotyped and live SARS-CoV-2 infection. Some reports have shown that the neutralizing antibody titers are strongly correlated with RBD-binding IgG ...
Adeno-associated virus (AAV) receptor (AAVR) is an essential receptor for the entry of multiple AAV serotypes with divergent rules; however, the mechanism remains unclear. Here, we determine the structures of the AAV1-AAVR and AAV5-AAVR complexes, revealing the molecular details by which PKD1 recognizes AAV5 and PKD2 is solely engaged with AAV1. PKD2 lies on the plateau region of the AAV1 capsid. However, the AAV5-AAVR interface is strikingly different, in which PKD1 is bound at the opposite side of the spike of the AAV5 capsid than the PKD2-interacting region of AAV1. Residues in strands F/G and the CD loop of PKD1 interact directly with AAV5, whereas residues in strands B/C/E and the BC loop of PKD2 make contact with AAV1. These findings further the understanding of the distinct mechanisms by which AAVR recognizes various AAV serotypes and provide an example of a single receptor engaging multiple viral serotypes with divergent rules.
The copolymerization of styrene and ethylene has been performed using a titanocene-based catalytic system of cyclopentadienyltitanium triphenoxide (CpTi(OPh)3) and methylaluminoxane (MAO). The catalyst system exhibited a high catalytic activity of 104−105 g (mof Ti·h)-1 and was found to selectively (more than 90 wt %) give an elastoplastic and amorphous styrene−ethylene (S−E) copolymer with a well-defined random/alternating microstructure and a single glass transition (T g) as thoroughly characterized by solvent fractionation, GPC, 13C NMR, DSC, and WAXD. Under the reaction conditions employed, up to 54.5 mol % of styrene could be introduced into the copolymer chains. The composition, microstructure, molecular weight of the copolymers, and catalytic activity of the copolymerization are strongly dependent upon the comonomer feed ratio, polymerization temperature (T p), CpTi(OPh)3/MAO mole ratio, and trimethylaluminum (TMA) content or structure in MAO. For 300 ⩽ Al/Ti < 1000, the copolymerization product was essentially the random S−E copolymer. For 1000 < Al/Ti ⩽ 2000, the copolymerization product was significantly SPS homopolymer. The results showed that 24.5−28.2 mol % TMA content in MAO (oligomerization degree (n) ≈ 18−20) was optimum for the copolymerization, but 30.2−35.7 mol % TMA in MAO (oligomerization degree (n) ≈ 24−28) for styrene syndiospecific homopolymerization, even in the presence of ethylene feed monomer. The external addition of TMA or triisobutylaluminum (TIBA) inhibited the copolymerization but promoted the styrene homopolymerization. ESR spectroscopic analysis combined with copolymerization results suggests the presence of a Ti(IV) active center which is responsible for the formation of polyethylene, a Ti(III) species which is active in the syndiospecific polymerization of styrene, and, moreover, the presence of a third intermediate which contributes to promoting the copolymerization of styrene with ethylene to produce S−E copolymer.
Titanocene complexes based on an amido-fluorenyl ligand bridged by a dimethylsilylene group, (η 1 :η 5 -C13H8SiMe2NCMe3)TiCl2 ( 3) and (η 1 :η 5 -C13H8SiMe2NCMe3)TiMe2 ( 5), have been synthesized. Reaction of 5 with 1 equiv of [Ph3C][B(C6F5)4] (2) was almost quantitative to give the "cationic" compound [(η 1 :η 5 -C13H8SiMe2NCMe3)TiMe] + [B(C6F5)4] -(1), as identified on the basis of elemental analyses and spectroscopic properties. The "cation" 1 was highly active and stereoselective in the copolymerization of ethylene (E) and styrene (S), depending upon the polymerization conditions, to produce predominantly a new microstructural E-S copolymer (together with some polyethylene homopolymer) with an activity of (0.65-1.58) × 10 5 g of bulk polymer/(mol of Ti‚mol of total monomers‚h). As thoroughly characterized by solvent extraction, GPC, 13 C NMR, DSC, and DMA, the E-S copolymer obtained by catalyst 1 proved to be a perfectly alternating copolymer with well-defined isotactic polystyrene structure, together with a single glass transition (Tg ) 30 °C) and melting temperature of 118 °C. The findings obtained by catalyst 1 suggest that the structure of the active species with the bulkier fluorenyl substituent and the following alternating site migratory insertion of comonomer in the chain propagation is responsible for the preferentially alternating, isotactic comonomer incorporation. the substituted bis(phenolate) ligand 2,2′-thiobis(6-tertbutyl-4-methylphenol) and MAO, afforded only a ran-
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